The present invention relates to biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists, to methods of using such compounds in the treatment of conditions such as hypertension and other diseases, and to pharmaceutical compositions containing such compounds.
The present invention provides biphenyl sulfonamide compounds of the following formula I, enantiomers (including atropisomers), diastereomers, salts and metabolites thereof: 
wherein: 
R2 is hydrogen, halogen, xe2x80x94CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, aryloxy alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, xe2x80x94CH(OR13)(OR14), xe2x80x94(CH2)wY; with the proviso that when R1 is B, R2 is not hydrogen, halogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, nitro, xe2x80x94(CH2)wNR19R20 or xe2x80x94NHSO2R22;
R3 is heteroaryl;
R4 and R5 are each independently alkyl, hydroxyalkyl, cycloalkyl, hydroxy substituted cycloalkyl, alkoxyalkyl, or hydroxy substituted alkoxyalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl ring which may be optionally substituted with one or more hydroxy group;
R6 is alkyl, hydroxyalkyl, haloalkyl, hydroxy substituted haloalkyl, cycloalkyl, hydroxy substituted cycloalkyl, (cycloalkyl)alkyl, hydroxy substituted (cycloalkyl)alkyl, aralkyl, alkoxy, hydroxy substituted alkoxy, alkoxyalkyl, hydroxy substituted alkoxyalkyl, or xe2x80x94NR16R17;
R7 is xe2x80x94(CH2)wxe2x80x94CO2R15, xe2x80x94(CH2)wxe2x80x94(Cxe2x95x90O)NR16R17, xe2x80x94(CH2)wxe2x80x94NR15(Cxe2x95x90O)NR16R17, xe2x80x94(CH2)wxe2x80x94CH2OH, xe2x80x94(CH2)wxe2x80x94(Cxe2x95x90O)R15, tetrazolyl, oxadiazolyl or triazolyl wherein said tetrazolyl, oxadiazolyl or triazolyl may optionally be substituted with hydrogen, alkyl, hydroxy or halogen;
R8, R9, R9a, R10 and R12 are each independently hydrogen, halogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, alkylthioalkyl, alkoxy or alkoxyalkyl, or R9 and R9a together with the carbon atom to which they are bonded form a cycloalkyl ring;
R11 and R11a are each independently hydrogen, alkoxy, or together form a carbonyl;
R13 and R14 are alkyl or together form a five to six-membered ring;
R15, R16 and R17 are independently hydrogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, aralkyl, heterocycloalkyl, aryl, heteroaryl or xe2x80x94(CH2)wQ, or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is heteroaryl, xe2x80x94COOH, xe2x80x94COOR18, xe2x80x94CONR19R20, xe2x80x94NR19R20, xe2x80x94NR19xe2x80x94OR20, xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94N(R19)-(alk)xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22, Q, R or S; 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, xe2x80x94CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, xe2x80x94CH(OR13)(OR14), or xe2x80x94(CH2)wY;
wherein said rings; aryl alone or as part of another group; or heteroaryl alone or as part of another group may each optionally be substituted by one or more hydrogen, halogen, cyano, alkyl, hydroxyalkyl, alkoxy, nitro or trifluoromethyl groups.
The compounds of the formula I and salts thereof may be used as combined endothelin and angiotensin receptor antagonists.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R15, R16, R17, R18, R19, R20, R21,R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, n, w, Y, Q, Z, and x are selected from the following definitions, are preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY, or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or (CH2)wY;
R3 is isoxazolyl, pyridizinyl, pyrazinyl or pyrimidinyl, each optionally substituted with one to three of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, haloalkyl, cycloalkyl or alkoxy;
R7 is xe2x80x94CO2R15, xe2x80x94(Cxe2x95x90O)NR16R17 or xe2x80x94CH2OH;
R8, R9, R10 and R12 are each independently hydrogen, halogen, alkyl, cycloalkyl, alkoxy or alkoxyalkyl;
R11 and R11a are each independently hydrogen, alkoxy, or together form a carbonyl;
R15, R16 and R17 are independently hydrogen, alkyl or cycloalkyl or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is xe2x80x94COOR18, xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, alkoxy or alkyl.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, n, w, Y, Q, Z, and x are selected from the following definitions, are more preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY; or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY;
R3 is isoxazolyl, optionally substituted with one or two of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, haloalkyl, cycloalkyl or alkoxy;
R7 is xe2x80x94C2R15 or xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9 and R10 are each independently hydrogen, halogen, alkyl, cycloalkyl alkoxy or alkoxyalkyl;
R11 and R11a together form a carbonyl;
R15, R16 and R17 are independently hydrogen, alkyl, or cycloalkyl or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 2;
w is 0, 1, or 2;
Y is xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21,(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R8, R10, R11, R11a, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, w, Y, Q, Z, and x are selected from the following definitions, are most preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY;
R3 is isoxazol-5-yl or isoxazol-3-yl independently substituted with two of following substituents: alkyl or halogen;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, halo alkyl, cycloalkyl or alkoxy;
R7 is xe2x80x94CO2R15 or xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9, and R10 are independently H, alkyl, cycloalkyl, alkoxy or alkoxyalkyl;
n is 2;
w is 0, 1, or 2;
Y is xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is 
x is 2;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.
Especially preferred are compounds where
R1 is selected from A, D, or E;
R2 is selected from alkyl, alkoxyalkyl, and haloalkoxyalkyl, and further selected from hydrogen when R1 is D;
R3 is isoxazol-3-yl independently substituted with two of following substituents: alkyl or halogen;
R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl;
R7 is xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9, and R10 are independently alkyl or alkoxy; and
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.
The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The terms xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one double carbon to carbon bond, such as ethenyl.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl group bonded through an oxygen (xe2x80x94Oxe2x80x94).
The term xe2x80x9caryloxyxe2x80x9d refers to an aryl group bonded through an oxygen (xe2x80x94Oxe2x80x94).
The term xe2x80x9cthioalkylxe2x80x9d refers to an alkyl group bonded through a sulfer (xe2x80x94Sxe2x80x94).
The term xe2x80x9ccarbonylxe2x80x9d refers to the group xe2x80x94(Cxe2x95x90O)xe2x80x94.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d refer to phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group. Aryl groups may be optionally substituted with one or more (such as one to three) of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, nitro or trifluoromethyl groups.
The term xe2x80x9ccycloalkylxe2x80x9d refers to fully saturated cyclic hydrocarbon groups having 3 to 8 ring carbon atoms.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine. Haloalkyl refers to an alkyl chain substituted with from one to three halogens.
The term xe2x80x9cheteroarylxe2x80x9d refers to furyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each of which may optionally be substituted where appropriate by one or more (such as one to three) of the following: hydrogen, halogen, cyano, alkyl, hydroxyalkyl, alkoxy, nitro or trifluoromethyl.
The terms xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocycloxe2x80x9d refer to optionally substituted, non-aromatic cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.
The term xe2x80x9cringxe2x80x9d encompasses homocyclic (i.e., as used herein, all the ring atoms are carbon) or xe2x80x9cheterocyclicxe2x80x9d (i.e., as used herein, the ring atoms include carbon and one to four heteroatoms selected from N, O and/or S, also referred to as heterocyclo), where, as used herein, each of which (homocyclic or heterocyclic) may be saturated or partially or completely unsaturated (such as heteroaryl), and each of which (homocyclic or heterocyclic) may optionally be substituted by one or more (such as one to three) hydrogen, halogen, cyano, alkyl, alkoxy, nitro or trifluoromethyl groups.
Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.
The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term xe2x80x9csalt(s)xe2x80x9d, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of formula I contains both a basic moiety and an acidic moiety, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed and are included within the term xe2x80x9csalt(s)xe2x80x9d as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
The compounds of formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
The compounds of formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term xe2x80x9cprodrugxe2x80x9d, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates. Any tautomers which may exist are also contemplated herein as part of the present invention.
All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons, e.g., atropisomers) and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
The present invention can be applied to the extensive prior art in the field of angiotensin antagonists to obtain additional novel compounds possessing potent antagonist activity at both endothelin and angiotensin receptors. In particular, a large number of groups (known to be useful within the field of angiotensin receptor antagonists) can be substituted at the R1 position of Formula I without departing from the scope of the present invention. The table below outlines examples of additional suitable R1 groups.
The compounds of the present invention may be prepared by methods such as those illustrated in the following Schemes I to XIII. Solvents, temperatures, pressures, and other reaction conditions may be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.
The following are the definitions of symbols used throughout Schemes I to XIII:
AA hydrogen, halogen (chloro, bromo, iodo) or xe2x80x94OSO2CF3;
BB suitable nitrogen protecting group, exemplified by methoxymethyl-[MOM], benzyloxymethyl-[BOM], 2-(trimethylsilyl)ethoxymethyl-[SEM], methoxyethoxymethyl-[MEM], or t-butyl groups;
DD Sn2 or Sn1 leaving group exemplified by halogen (Cl, Br, I) and sulfonates (xe2x80x94OSO2-aryl (e.g., xe2x80x94OSO2Ph or xe2x80x94OSO2PhCH3), or xe2x80x94OSO2-alkyl (e.g., xe2x80x94OSO2CH3 or xe2x80x94OSO2CF3));
EE halogen (chloro, bromo, iodo) or xe2x80x94OSO2CF3;
GG boronate ester or boronic acid, or trialkylstannane;
HH metal atom such as tin, zinc, magnesium or lithium as part of an organometallic compound used as an intermediate for transition metal mediated arylxe2x80x94aryl coupling reactions;
JJ xe2x80x94CN, xe2x80x94CHO, or xe2x80x94CO2R20 wherein R20 is hydrogen or C1 to C3 alkyl.
Exemplary conditions for forming and removing suitable nitrogen protecting groups may be found in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991, pp. 309-405. One skilled in the art can also recognize that the heteroaryl sulfonamidexe2x80x94NH in compounds of the invention will also have carboxylic acid character, and accordingly, methods used to protect carboxylic acids may be applicable to protecting the nitrogen NH of the sulfonamides in the invention, including intermediates to compounds of formula I. Exemplary conditions for forming and removing suitable carboxylic acid protecting groups may be found in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991, pp. 175-276.
Compounds of formula I may be prepared from the deprotection of a compound of formula II wherein BB is a suitable nitrogen protecting group. Exemplary conditions for deprotection, and nitrogen protecting groups, may be found in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991, pp. 309-405. Preferred nitrogen protecting groups are the methoxymethyl (MOM), methoxyethoxymethyl (MEM), and 2-(trimethylsilyl)ethoxymethyl (SEM) groups.
Compounds of formula II may be prepared from a palladium catalyzed coupling of a compound of formula III with a compound of formula VIII, in the presence of a suitable base in an inert solvent. Exemplary palladium catalysts include tetrakis(triphenylphosphine) palladium(0), palladium(II) chloride or palladium(II) acetate. The preferred palladium catalyst is tetrakis(triphenylphosphine) palladium(0). Exemplary bases include tertiary amines, such as, but not limited to, triethylamine, or aqueous potassium, sodium, or cesium carbonate. The preferred base is aqueous sodium carbonate. Exemplary solvents include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, or straight chain alcohols, or a combination thereof. The preferred solvent is a mixture of toluene and ethanol. Exemplary reaction temperatures are between about 25xc2x0 C. to 125xc2x0 C., preferably between about 65xc2x0 C. and 110xc2x0 C.
Compounds of formula III may be prepared from a compound of formula IV via displacement of the leaving group (DD) by the conjugate base of a compound R1xe2x80x94H, wherein R1 is as previously defined, using a base in an inert solvent. Exemplary bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, or alkyl lithiums. The preferred base is sodium hydride. Exemplary inert solvents include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether), or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Exemplary reaction temperatures are between about 0xc2x0 C. to 154xc2x0 C., preferably between about 65xc2x0 C. and 110xc2x0 C.
Compounds of formula III may also be prepared via a Mitsunobu reaction between a compound of formula VI and the conjugate acid R1xe2x80x94H, preferably using a phosphine and oxidizing agent, in an inert solvent. Exemplary phosphines include trialkylphosphines, triarylphosphines and polymer supported triarylphosphines. The preferred phosphine is triphenylphosphine. Exemplary oxidizing reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate, or carbon tetrabromide. The preferred oxidizing reagent is diethyl azodicarboxylate. Exemplary inert solvents include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether), acetonitrile or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Exemplary reaction temperatures are between about 0xc2x0 C. to 154xc2x0 C., preferably between about 20xc2x0 C. and 65xc2x0 C.
Compounds of formula IV (especially, where DD is xe2x80x94OSO2Ph, xe2x80x94OSO2PhCH3, xe2x80x94OSO2CH3, xe2x80x94OSO2CF3) may be prepared from the reaction of a compound of formula VI with ClSO2Ph, ClSO2PhCH3, ClSO2CH3 or (CF3SO2)2O in the presence of a base in an inert solvent.
Compounds of formula VI may be prepared from reduction of a compound of formula VII using a suitable reducing agent in an inert solvent.
Compounds of formula VII are either commercially available or available by means known to one skilled in the art.
Compounds of formula VIII may be prepared via lithiation of a compound of formula IX wherein AA is hydrogen or a halogen (chloro, bromo, iodo), and reacting the resulting aryl lithium with an appropriate borate derivative.
Compounds of formula IX may be prepared via the protection of the nitrogen in a compound of formula XI. Exemplary nitrogen protecting groups and methods of protecting the nitrogen are similar to those for protecting amines, such as those described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991.
Compounds of formula XI may be prepared from the reaction of a compound of formula XII with a compound R3xe2x80x94NH2.
Compounds of the formula XII are either commercially available or available by means known to one skilled in the art. 
Compounds of formula I may be prepared from the deprotection of a compound of formula II as described in Scheme I.
Compounds of formula II may be prepared from a compound of formula XIV via displacement of the leaving group (DD) by the conjugate base of a compound R1xe2x80x94H, wherein R1 is as previously defined, using a base in an inert solvent. Exemplary bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, or alkyl lithiums. The preferred base is sodium hydride. Exemplary inert solvents include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether), or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Exemplary reaction temperatures are between about 0xc2x0 C. to 154xc2x0 C., preferably between about 25xc2x0 C. and 110xc2x0 C.
Compounds of formula II may also be prepared via a Mitsunobu reaction between a compound of formula XV and the conjugate acid R1xe2x80x94H using a phosphine and oxidizing agent in an inert solvent. Exemplary phosphines include trialkylphosphines, triarylphosphines and polymer supported triarylphosphines. The preferred phosphine is triphenylphosphine. Exemplary oxidizing reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate, or carbon tetrabromide. The preferred oxidizing reagent is diethyl azodicarboxylate. Exemplary inert solvents include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether), acetonitrile or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Exemplary reaction temperatures are between about 0xc2x0 C. to 154xc2x0 C., preferably between about 20xc2x0 C. and 65xc2x0 C.
Compounds of formula XIV may be prepared from compounds of formula XV using methods well known in the art. For example, compounds of formula XIV (DD=Br) may be prepared by the treatment of compound XV with carbon tetrabromide and triphenylphosphine in a suitable solvent such as toluene or tetrahydrofuran.
Compounds of formula XV may be prepared from reduction of a compound of formula XVI using a suitable reducing agent in an inert solvent. R2 is preferably not an amide, an ester, a carboxylic acid or an aldehyde during this operation.
Compounds of formula XVI may be prepared from a palladium catalyzed coupling of a compound of formula VII with a compound of formula IX in the presence of a suitable base and an inert solvent as described in Scheme I.
Compounds of formula VII are available by means known to one skilled in the art. 
Compounds of formula XVII (which are compounds of formula I wherein R2 is R2a where R2a is xe2x80x94CH2N(R21)(Cxe2x95x90O)N(R19)R20, xe2x80x94CH2N(R21)(Cxe2x95x90O)OR18 or xe2x80x94CH2N(R21)(Cxe2x95x90O)R22), may be prepared from compounds of formula XVIII (also compounds of formula I, where R2 is xe2x80x94CH2NHR21) by reaction of a compound of formula XVIII with an active ester (i.e., from a carboxylic acid such as R22COOH in the presence of a suitable coupling agent such as dicyclohexylcarbodimide (DCC)), or an acid chloride (i.e., R22(Cxe2x95x90O)Cl), or an isocyanate (i.e., R19Nxe2x95x90Cxe2x95x90O), or a chloroformate (i.e., R18O(Cxe2x95x90O)Cl) in the presence of a suitable base such as triethylamine and catalyst such as 4-dimethylaminopyridine in an inert solvent. This step may, for example, be conducted combinatorially and a library of such compounds created.
Compounds of formula XVIII may be prepared from reductive amination of compounds of formula XIX (compounds of formula I where R2 is xe2x80x94CHO) using a primary amine such as R21NH2 in the presence of a suitable reducing agent such as sodium triacetoxyborohydride in an inert solvent.
Compounds of formula XIX may be prepared by deprotection of compounds of formula XX wherein BB is a suitable nitrogen protecting group as described in Scheme I.
Compounds of formula XX may be prepared from a palladium catalyzed coupling of a compound of formula XXI with a compound of formula VIII in the presence of a suitable base and an inert solvent as described in Scheme I.
Compounds of formula XXI may be prepared in two steps from a compound of formula XXIII, first by displacement of the leaving group (DD) by the conjugate base of a compound R1xe2x80x94H, wherein R1 is as previously defined using a suitable base in an inert solvent as described in Scheme I to provide a compound of formula XXII. Subsequent deprotection of the acetal in a compound of formula XXII using methods known in the art is employed to provide a compound of formula XXI.
Compounds of formula XXII may also be prepared via a Mitsunobu reaction between a compound of formula XXIV and the conjugate acid R1xe2x80x94H using a phosphine and oxidizing agent in an inert solvent. Exemplary phosphines include trialkylphosphines, triarylphosphines and polymer supported triarylphosphines. Exemplary oxidizing reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate, or carbon tetrabromide. Exemplary inert solvents include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether), acetonitrile or N,N-dimethylformamide.
Compounds of formula XXIII may be prepared from compounds of formula XXIV using methods well known in the art. For example, compounds of formula XXIII (DD=Br) may be prepared by the treatment of compound XXIV with carbon tetrabromide and triphenylphosphine in a suitable solvent such as toluene or tetrahydrofuran.
Compounds of formula XXIV may be prepared in two steps from compound XXV via a partial reduction of the nitrile group to the aldehyde using a suitable reducing agent such as diisobutylaluminum hydride, with subsequent reduction of the aldehyde to hydroxymethyl using an agent such as sodium borohydride.
Methods for the preparation of compounds XXV and XXVI are known in the art [H.-Y. Zhang, et al., Tetrahedron, 50, 11339-11362 (1994)]. 
Compounds of formula XXIX (which are compounds of formula I where R2 is xe2x80x94CH2Y) may be prepared from the deprotection of a compound of formula XXX such as is described in Scheme I.
Compounds of formula XXX may be prepared from a compound of formula XXXI via displacement of the leaving group (DD) by the conjugate base of a compound Yxe2x80x94H, wherein Y is as previously defined using a base in an inert solvent. Exemplary bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, or alkyl lithiums. The preferred base is sodium hydride.
Compounds of formula XXXI may be prepared from compounds of formula XX using methods well known in the art. For example, compounds of formula XXXI (DD=Br) may be prepared from compound XX in two steps: first by reducing the aldehyde to a hydroxymethyl group using a suitable reducing agent such as sodium borohydride, and second, conversion of the hydroxymethyl group to the bromomethyl function using carbon tetrabromide and triphenylphosphine in a suitable solvent such as toluene or tetrahydrofuran. 
Compounds of formula XXXII (which may be employed, for example, in the methods of the preceding Schemes) may be prepared by cyclization of compounds of formula XXXIII in the presence of orthoester XXXIV using a catalytic amount of a weak acid such as acetic acid. Exemplary reaction temperatures are between about 25xc2x0 C. to 154xc2x0 C., preferably between about 60xc2x0 C. and 110xc2x0 C.
Compounds of formula XXXIII (e.g., where R13 and R14, together with the atoms to which they are bonded, form the five-membered ring 
may be prepared from compounds of formula XXXVI in two steps: (1) acylation of compound XXXVI with an N-protected amino acid in the presence of a suitable coupling agent such as dicyclohexylcarbodimide (DCC) or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) in a suitable solvent such as N,N-dimethylformamide, and (2) removal of the protecting group. Suitable conditions and suitable nitrogen protecting groups and the corresponding deprotection conditions may be found in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991, pp. 309-405.
Compounds of formula XXXVI may be prepared via reduction of a compound of formula XXXVII using an appropriate reducing agent such as diborane or lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran.
Compounds of formula XXXVII may be prepared from compounds of formula XXXVIII as described in Scheme III.
Compounds of formula XXXVIII may be prepared by methods known in the art. 
Compounds of formula I may be prepared from the deprotection of a compound of formula II as described in Scheme I.
Compounds of formula II may be prepared by a palladium catalyzed coupling of a compound of formula IX (as described in Scheme I) wherein AA here is xe2x80x94OSO2CF3 or a halogen (chlorine, bromine, or iodine; preferably bromine or iodine) with a compound of formula XXXIXa, wherein GG is a boronic acid or ester, in the presence of a base and an inert solvent as described in Scheme I.
Compounds of formula II may also be prepared by a palladium or nickel catalyzed coupling of a compound of formula IX (as described in Scheme I) wherein AA is a halogen (chlorine, bromine, or iodine; preferably bromine or iodine) with a compound of formula XXXIXb wherein HH is a suitable metal atom bearing appropriate ligands. Exemplary metal atoms include tin, zinc, magnesium, and lithium. Exemplary catalysts include tetrakis(triphenylphosphine)palladium(O) and dichlorobis(triphenylphosphine)nickel(II).
Compounds of formula XXXIXa or XXXIXb may be prepared via lithiation of a compound of formula III wherein EE is a halogen (chlorine, bromine, or iodine; preferably bromine or iodine), then reacting the resulting aryl lithium with an appropriate borate derivative or with an appropriate zinc, tin, or magnesium reagent.
Compounds of formula III may be prepared by the methods described in Scheme I. 
Compounds of formula I may be prepared from the thermal reaction of a compound of formula XL with a heterocyclic compound of formula R3xe2x80x94X, wherein X is a halogen (fluorine, chlorine, bromine, or iodine), in the presence of a base and an inert solvent. Exemplary bases include sodium hydride, potassium carbonate, potassium hydride, and potassium bis(trimethylsilyl)amide, preferably sodium hydride. Exemplary solvents include N,N-dimethylformamide and N,N-dimethylacetamide. Exemplary reaction temperatures are between about 80xc2x0 C. and 150xc2x0 C., preferably between 110xc2x0 C. and 130xc2x0 C.
Compounds of formula I may also be prepared from the reaction of a compound of formula XL with a heterocyclic compound of formula R3xe2x80x94X, wherein X is a halogen (chlorine, bromine, or iodine), in the presence of a palladium catalyst, a phosphine ligand, a base, and an inert solvent. Exemplary palladium catalysts include palladium acetate and tris(dibenzylideneacetone)palladium(0), and the preferred palladium catalyst is palladium acetate. The preferred phosphine ligand is 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl. Exemplary bases include sodium hydride and sodium t-butoxide. The preferred base is sodium hydride. Exemplary reaction temperatures are between about 20xc2x0 C. and 110xc2x0 C., preferably between 85xc2x0 C. and 110xc2x0 C.
Compounds of formula XL may be prepared by deprotection of a compound of formula XLI, wherein BB is a suitable nitrogen protecting group. Exemplary conditions for protection and deprotection of nitrogen functionalities may be found in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, 1991, pp. 309-405. The preferred protecting group BB for Scheme VII is tertiary-butyl. Exemplary deprotection conditions include the use of acids, such as trifluoroacetic acid.
Compounds of formula XLI may be prepared by a palladium catalyzed coupling of a compound of formula III (as described in Scheme I) wherein EE is a halogen (chlorine, bromine, or iodine; preferably bromine or iodine) with a compound of formula XLII, wherein GG is a boronic acid or ester, in the presence of a base and an inert solvent as described in Scheme I.
Compounds of formula XLII may be prepared via the lithiation of a compound of formula XLIII in an inert solvent, followed by reacting the resulting aryl lithium with an appropriate borate derivative. Exemplary reagents for the lithiation reaction include n-butyllithium and t-butyllithium. Exemplary solvents include ethers such as tetrahydrofuran, either alone or in combination with hydrocarbon solvents such as hexane. The preferred solvent is a mixture of tetrahydrofuran and hexane.
Compounds of formula XLIII are either commercially available or available by means known to one skilled in the art. 
Compounds of formula XXIX (which are certain compounds of formula I where R2 is xe2x80x94CH2Y, as described in Scheme IV) may be prepared from a compound of formula XIX (which is a compound of formula I where R2 is xe2x80x94CHO, as described in Scheme III) via a two step process: 1) reductive amination of XIX in the presence of a primary amine R30NH2, wherein R30 is carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, or aminoalkyl, using a suitable reducing agent such as sodium triacetoxyborohydride, yields an intermediate amine; 2) subsequent cyclization using an appropriate cyclization reagent yields a compound of formula XXIX. When R30 is carboxyalkyl, appropriate cyclization reagents include carbodiimides such as diisopropylcarbodiimide. When R30 is hydroxyalkyl or aminoalkyl, appropriate cyclization reagents include phosgene and 1,1xe2x80x2-carbonyldiimidazole. When R30 is alkoxycarbonylalkyl, appropriate cyclization reagents include tertiary amine bases such as triethylamine and N,N-diisopropylethylamine.
Compounds of formula XIX may be prepared via deprotection of a compound of formula XX as described in Scheme III.
Compounds of formula XXIX may also be prepared by deprotection of a compound of formula XXX as described in Scheme I.
Compounds of formula XXX may be prepared from a compound of formula XX, using the two step process described above for the formation of compounds of formula XXIX from a compound of formula XIX. 
Compounds of formula XLIV (which are compounds of formula I wherein R1 is D as defined for formula I) may be prepared from the deprotection of a compound of formula XLV as described in Scheme I.
Compounds of formula XLV may be prepared via the acylation of a compound of formula XLVI using either a carboxylic acid such as R6COOH in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, or the corresponding acid chloride or acid anhydride in the presence of a suitable base such as triethylamine.
Compounds of formula XLVI may be prepared from reduction of a compound of formula XLVII in the presence of a primary amine such as H2NCHR7R9 in the presence of a suitable reducing agent such as sodium triacetoxyborohydride.
Compounds of formula XLVII may be prepared via reduction of a compound of formula XVI, as described in Scheme II, wherein JJ is xe2x80x94CN, or xe2x80x94CO2R20 wherein R20 is hydrogen or C1 to C3 alkyl, using means known to one skilled in the art.
Compounds of formula XLVII may also be prepared via oxidation of a compound of formula XV, as defined in Scheme II, using means known to one skilled in the art. 
Compounds of formula XLIV (which are compounds of formula I wherein R1 is D as defined for formula I) may be prepared by the acylation of a compound of formula LXI using either a carboxylic acid such as R6COOH in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, or the corresponding acid chloride or acid anhydride in the presence of a suitable base such as triethylamine.
Compounds of formula LXI may be prepared by the reduction of a compound of formula LXII in the presence of a primary amine such as H2NCHR7R9 in the presence of a suitable reducing agent such as sodium triacetoxyborohydride.
Compounds of formula LXII may be prepared via deprotection of a compound of formula LXIII (which is a compound of formula XVI wherein JJ is CHO), as described in Scheme I. 
Compounds of formula LXIV (which are compounds of formula I wherein R2 is xe2x80x94N(R19)R20) may be prepared via reduction of a compound of formula LXV in the presence of an aliphatic, aromatic, or heteroaromatic aldehyde using a suitable reducing agent such as sodium triacetoxyborohydride.
Compounds of formula LXV (which are compounds of formula I wherein R2 is xe2x80x94NHR19) may be similarly prepared via reduction of a compound of formula LXVI in the presence of an aliphatic, aromatic, or heteroaromatic aldehyde using a suitable reducing agent such as sodium triacetoxyborohydride.
Compounds of formula LXVI (which are compounds of formula I wherein R2 is xe2x80x94NH2) may be prepared by reduction of a compound of formula LXVII using a suitable reducing agent such as tin (II) chloride dihydrate in a suitable solvent such as ethyl acetate.
Compounds of formula LXVII (which are compounds of formula I wherein R2 is xe2x80x94NO2) may be prepared by deprotection of a compound of formula LXVIII as described in Scheme I. Compounds of formula LXVIII (which are compounds of formula II wherein R2 is xe2x80x94NO2) may be prepared by the methods described for the preparation of compounds of formula II in Schemes I and II. 
Compounds of formula LXIX (which are compounds of formula I wherein R2 is xe2x80x94N(R21)(Cxe2x95x90O)R22) may be prepared via acylation of a compound of formula LXVa (prepared as described in Scheme XI for a compound of formula LXV) using either a carboxylic acid such as R22COOH in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, or the corresponding acid chloride or acid anhydride in the presence of a suitable base such as triethylamine.
Compounds of formula LXX (which are compounds of formula I wherein R2 is xe2x80x94N(R21)SO2R22) may be prepared via sulfonylation of a compound of formula LXVa using either a sulfonyl chloride such as R22SO2Cl or the corresponding sulfonic anhydride, in the presence of a suitable base such as triethylamine. 
Compounds of formula LXXI (which are compounds of formula I wherein R2 is xe2x80x94CH2N(R21)(SO2R22)) may be prepared via sulfonylation of a compound of formula XVIII (prepared as described in Scheme III) using either a sulfonyl chloride such as R22SO2Cl or the corresponding sulfonic anhydride in the presence of a suitable base such as triethylamine.
The present invention further provides the following novel compounds, which may be employed as intermediates in the preparation of compounds of the formula I and salts thereof: 
wherein R2, R3, R101, R102, R103, and R104 are as defined for a compound of formula I, R50 is hydroxy, chloro, bromo, iodo, xe2x80x94OSO2-alkyl, or xe2x80x94OSO2-aryl, and R51 is hydrogen, xe2x80x94CH2OCH2CH2OCH3, xe2x80x94CH2OCH2CH2Si(CH3)3, xe2x80x94CH2OCH3, xe2x80x94CH2OCH2-aryl, or other suitable nitrogen protecting group; 
wherein R1, R2, R3, R101, R102, R103, and R104 are as defined for a compound of formula I and BB is xe2x80x94CH2OCH2CH2OCH3, xe2x80x94CH2OCH2CH2Si(CH3)3, xe2x80x94CH2OCH3, xe2x80x94CH2OCH2-aryl, or other suitable nitrogen protecting group; and 
wherein R1, R2, R101, and R102 are as defined for a compound of formula I, and R52 is chloro, bromo, iodo, or xe2x80x94OSO2CF3.
The present invention also provides the following novel method for the preparation of a compound of the formula I or salt thereof, wherein said method comprises at least one of the following steps:
a) displacement of a leaving group R50 via the anion of a compound R1xe2x80x94H from a compound of the formula 
xe2x80x83wherein R1, R2, R3, R101, R102, R103, and R104 are as defined for a compound of formula I, R50 is hydroxy, chloro, bromo, iodo, xe2x80x94OSO2-alkyl or xe2x80x94OSO2-aryl, and R51 is hydrogen or a suitable nitrogen protecting group, using a Mitsunobu reaction or Sn1 or Sn2 displacement reaction, with removal of 5 said nitrogen protecting group as appropriate;
b) removal of the nitrogen protecting group R51 from a compound of formula 
xe2x80x83wherein R1, R2, R3, R101, R102, R103, and R104 are as defined for a compound of formula I, and R51 is a suitable nitrogen protecting group;
c) organometallic coupling of a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83wherein R1, R2, R3, R101, R102, R103, and R104 are as defined for a compound of formula I and R51 is a suitable nitrogen protecting group. R52 is chloro, bromo, iodo or xe2x80x94OSO2CF3 and R54 is a boronic acid, boronic ester or stannane derivative. Or R52 is a boronic acid, boronic ester or stannane derivative, and R54 is chloro, bromo, iodo or xe2x80x94OSO2CF3;
d) acylation of a compound of the formula 
xe2x80x83wherein R1, R3, R101, R102, R103, and R104 are as defined for a compound of formula I, and R51 is hydrogen or a suitable nitrogen protecting group, with an acylating agent of the formula R55xe2x80x94(Cxe2x95x90O)R22, R19Nxe2x95x90Cxe2x95x90O, R55xe2x80x94CO2R18, R55SO2R22, wherein R18, R19 and R22 are as defined for a compound of formula I and R55 is an activating group for an acid, or made using an acid activating agent, with removal of said nitrogen protecting group as appropriate; or
e) reductive amination of a compound of formula 
xe2x80x83wherein R1, R3, R101, R102, R103, and R104 are as defined for a compound of formula I, and R51 is hydrogen or a suitable nitrogen protecting group, with an amine of the formula 
xe2x80x83wherein R23, R24, and x are as defined for a compound of formula I, with removal of said nitrogen protecting group as appropriate.
The compounds of formula I and salts thereof are antagonists of both endothelin (especially, ET-1) and angiotensin II (especially, subtype AT1) receptors (xe2x80x9cdual angiotensin endothelin receptor antagonistsxe2x80x9d) and are useful in treatment of conditions associated with increased ET levels and/or increased angiotensin II levels and of all endothelin-dependent or angiotensin II-dependent disorders. They are thus useful as antihypertensive agents. By the administration of a composition having one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. They are also useful in portal hypertension, hypertension secondary to treatment with erythropoietin and low renin hypertension.
The compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute (such as ischemic, nephrotoxic, or glomerulonephritis) and chronic (such as diabetic, hypertensive or immune-mediated) renal failure, diabetic nephropathy, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and the like. The compounds of this invention are also useful in the treatment of disorders related to paracrine and endocrine function. The compounds of this invention are also useful in the treatment of diabetic nephropathy, hypertension-induced nephropathy, and IGA-induced nephropathy.
The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock as well as hemorrhagic shock. The compounds of the present invention are also useful in alleviation of pain associated cancer, such as the pain associated with prostate cancer, and bone pain associated with bone cancer. The compounds of the present invention are further useful in the prevention and/or reduction of end-organ damage associated the cell-poliferative effects of endothelin.
The compounds of the present invention are also useful in hypoxic and ischemic disease and as anti-ischemic agents for the treatment of, for example, cardiac, renal and cerebral ischemia and reperfusion (such as that occurring following cardiopulmonary bypass surgery), coronary and cerebral vasospasm, and the like.
In addition, the compounds of this invention are also useful as anti-arrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti-atherosclerotic and anti-arteriosclerotic agents (including anti-transplantation arteriosclerotic agents); additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents. The compounds of this invention may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud""s disease, intermittent claudication and Takayashu""s disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of primary pulmonary hypertension (e.g., plexogenic, embolic) in adults and in the newborn and pulmonary hypertension secondary to heart failure, radiation and chemotherapeutic injury, or other trauma; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn""s disease, gastric mucosal damage, ulcer, inflammatory bowel disease and ischemic bowel disease; treatment of gall bladder or bile duct-based diseases such as cholangitis; treatment of pancreatitis; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedure including transplantation and stenting; therapy for congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatotoxicity and sudden death. The compounds of this invention are useful in the treatment of sickle cell disease including the initiation and/or evolution of the pain crises of this disease; treatment of the deleterious consequences of ET-producing tumors such as hypertension resulting from hemangiopericytoma; treatment of early and advanced liver disease and injury including attendant complications (e.g., hepatotoxicity, fibrosis and cirrhosis); treatment of spastic diseases of the urinary tract and/or bladder; treatment of hepatorenal syndrome; treatment of immunological diseases involving vasculitis such as lupus, systemic sclerosis, mixed cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and hepatotoxicity. The compounds of this invention are useful in therapy for metabolic and neurological disorders; cancer; insulin-dependent and non insulin-dependent diabetes mellitus; neuropathy; retinopathy; epilepsy; hemorrhagic and ischemic stroke; bone remodeling; psoriasis; and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).
The compounds of this invention are additionally useful in the treatment of disorders involving bronchoconstriction and disorders of chronic or acute pulmonary inflammation such as chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS).
The compounds of this invention are also useful in the treatment of sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially, the corpus cavernosum.
The compounds of this invention are also useful in the treatment of dementia, including Alzheimer""s dementia, senile dementia and vascular dementia.
Additionally the compounds of the present invention are further useful in the reduction of general morbidity and/or mortality as a result of the above utilities.
The present invention thus provides methods for the treatment of all endothelin-dependent or angiotensin II-dependent disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor. Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a human of from about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably from about 0.5 to about 25 mg/kg of body weight (or from about 1 to about 2500 mg, preferably from about 5 to about 500 mg) of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to endothelin-dependent or angiotensin II-dependent disorders.
The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating an endothelin-dependent or angiotensin II-dependent disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation or called for by accepted pharmaceutical practice.
The compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally. For example, the active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit dosage of a compound or mixture of compounds of formula I or in topical form for wound healing (0.01 to 5% by weight compound of formula I, 1 to 5 treatments per day). They may be compounded in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., or with a topical carrier. The compounds of formula I can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration. About 0.1 to 500 milligrams of a compound of formula I may be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is preferably such that a suitable dosage in the range indicated is obtained.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). For example, the compounds of the invention may be administered topically to treat peripheral vascular diseases and as such may be formulated as a cream or ointment.
The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of endothelin-dependent or angiotensin II-dependent disorders. For example, the compounds of this invention can be formulated in combination with endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists such as ifetroban; potassium channel openers; thrombin inhibitors (e.g., hirudin and the like); growth factor inhibitors such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants such as warfarin, low molecular weight heparins such as enoxaparin, Factor VIIa inhibitors, and Factor Xa inhibitors such as those described in U.S. Ser. No. 09/496,571 filed Feb. 2, 2000 (attorney docket HA 723); renin inhibitors; angiotensin converting enzyme (ACE) inhibitors such as captopril, zofenopril, fosinopril, ceranapril, alacepril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants such as questran; niacin; anti-atherosclerotic agents such as ACAT inhibitors; MTP inhibitors such as those described in U.S. Ser. No. 09/007,938 filed Jan. 16, 1998 (attorney docket HX 91); calcium channel blockers such as amlodipine besylate; potassium channel activators; alpha-adrenergic agents, beta-adrenergic agents such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzothiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds; thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), biguanide/glyburide combinations such as those described in U.S. Ser. No. 09/432,465 filed Nov. 3, 1999 (attorney docket LA 46) and U.S. Ser. No. 09/460,920 filed Dec. 14, 1999 (attorney docket LA 46a); thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists such as spironolactone and eplerenone; growth hormone secretagogues such as those described in U.S. Ser. No. 09/417,180 filed Oct. 12, 1999 (attorney docket LA 25) and U.S. Ser. No. 09/506,749 filed Feb. 18, 2000 (attorney docket LA 26); aP2 inhibitors such as those described in U.S. Ser. No. 09/391,053 filed Sep. 7, 1999 (attorney docket LA 24a) and U.S. Ser. No. 09/390,275 filed Sep. 7, 1999 (attorney docket LA 24b); digitalis; ouabian; non-steroidal antiinflammatory drugs (NSAIDS) such as aspirin and ibuprofen; phosphodiesterase inhibitors such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil); protein tyrosine kinase inhibitors; antiinflammatories; antiproliferatives such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate and mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as paclitaxel (Taxol(copyright)), docetaxel (Taxotere(copyright)), and epothilones A-F or their analogs or derivatives; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatin); cyclosporins; steroids such as prednisone or dexamethasone; gold compounds; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-alpha inhibitors such as tenidap; anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel) rapamycin (sirolimus or Rapamune), leflunimide (Arava); and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx).
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. The compounds of this invention may also be formulated with, or useful in conjunction with, antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomerular contraction and nephrotoxicity secondary to such compounds. The compounds of this invention may also be used in conjunction with hemodialysis.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The following assays may be employed in ascertaining the degree of activity of a compound (xe2x80x9cdrugxe2x80x9d) as an endothelin and angiotensin II receptor antagonist. Compounds described in the following Examples have been tested in these assays, and have shown activity.
ETA/B Attached Cell Binding Assay
CHO-K1 cells expressing either the human endothelin A or endothelin B receptor were cultured in Ham""s F12 media (Gibco/BRL, Grand Island, N.Y.) with 10% fetal bovine serum (Hyclone), supplemented with 300 xcexcg/mL Geneticin (G-418 Gibco BRL Products, Grand Island, N.Y.) and maintained at 37xc2x0 C. with 5% CO2 in a humidified incubator. Twenty four hours prior to assay, the cells were treated with 0.25% trypsin-EDTA and were seeded in Falcon, 96 well tissue culture plates at a density of 1.8xc3x97104 cells/well (the monolayer should reach 80-90% confluency by the day of assay).
In the attached cell assay, culture media was aspirated from each well and the monolayers were washed with 50 xcexcl of PBS (Mg++, Ca++ free). The binding assay was performed in a total volume of 125 xcexcl consisting of assay buffer (50 mM Tris, pH 7.4, including 1% BSA, and 2 xcexcM phosphoramidon), and 25 xcexcl of either 500 nM ET-1 (to define nonspecific binding) or competing drug. The reaction was initiated with the addition of 25 xcexcl of 0.25 nM [125I]-ET-1 (New England Nuclear). Incubation was carried out with gentle orbital shaking, at 4xc2x0 C., reaching equilibrium at 4 hours. The reaction was terminated by aspiration of the reaction buffer and two subsequent washes with cold PBS (Mg++, Ca++ free). The cells were dissociated by the addition of 100 xcexcl of 0.5N NaOH followed by incubation for 40 minutes. Samples were then transferred from the 96 well format into tubes for counting in a Cobra gamma counter (Packard). Data was analyzed with curve fitting software by Sigma plot.
RASMC Binding Assay
Assays were conducted in a total volume of 250 xcexcL in 96 well microtitre plates. The incubation mixture contained 50 xcexcL [125]I-Sar-Ile-Angiotensin II (0.2 nM), 25 xcexcL of drug dissolved in DMSO, or angiotensin II (1 xcexcM) to define non-specific binding. Binding to rat aortic smooth muscle cells (RASMCs) was conducted in RPMI media (Gibco BRL Products, Grand Island, N.Y.) containing 0.1% BSA for 2 hours at room temperature with continuous shaking. Unbound radioligand was washed from the wells. The RASMCs with bound radioligand are lysed with 1% Triton X and 0.1% BSA in distilled water for 15 minutes at room temperature with continuous shaking. The solution in each well was transferred to tubes and placed in a gamma counter.
Compounds within the scope of this invention include compounds that have an IC50 concentration of less than 100 micromolar versus either or both [125]I-Sar-Ile-Angiotensin II or [125I]-ET-1, ideally against both ligands. Preferred compounds within the scope of this invention are compounds that have an IC50 concentration of less than 5 micromolar versus either or both [125]I-Sar-Ile-Angiotensin II or [125I]-ET-1, ideally against both ligands. More preferred compounds within the scope of this invention are compounds that have an IC50 concentration of less than 1 micromolar versus either or both [125]I-Sar-Ile-Angiotensin II or [125I]-ET-1, ideally against both ligands.
All documents cited in the present specification are incorporated herein by reference in their entirety.
The following Examples illustrate embodiments of the present invention, and are not intended to limit the scope of the claims. Abbreviations employed herein are defined below. Compounds of the Examples are identified by the example and step in which they are prepared (for example, xe2x80x9c1Axe2x80x9d denotes the title compound of step A of Example 1), or by the example only where the compound is the title compound of the example (for example, xe2x80x9c4xe2x80x9d denotes the title compound of Example 4). Compounds prepared for use as synthetic intermediates are identified by the Preparation number and step in which they appear, prefaced by the letter xe2x80x9cP.xe2x80x9d For example, xe2x80x9cP1Axe2x80x9d denotes the compound generated in step A of Preparation 1, while xe2x80x9cP1xe2x80x9d denotes the title compound of Preparation 1.
Abbreviations
Ac=acetyl
(S)-BINAP=(S)-(xe2x88x92)2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl
BOC=t-butoxycarbonyl
n-Bu=n-butyl
BSA=bovine serum albumin
CDI=1,1xe2x80x2 carbonyldiimidazole
d=days
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
DIBAL-H=diisobutylaluminum hydride
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EDCI=1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride
EDTA=ethylenediaminetetraacetic acid
eq=equivalents
Et=ethyl
ET=endothelin
ET-1=endothelin-1
EtOAc=ethyl acetate
EtOH=ethanol
h=hours
Me=methyl
MEM=methoxyethoxymethyl
MeOH=methanol
min=minutes
mp=melting point
Ms=methanesulfonyl
NBS=N-bromosuccinimide
PBS=phosphate buffered saline
Ph=phenyl
n-Pr=n-propyl
SEM=2-(trimethylsiloxy)ethoxymethyl
Rochelle""s salt=potassium sodium tartrate tetrahydrate
RT=room temperature
TFA=trifluoroacetic acid
THF=tetrahydrofuran
The following General Methods were employed in the Preparations and Examples.
ArBr+Arxe2x80x2B(OR)2xe2x86x92Arxe2x80x94Arxe2x80x2
R=H, alkyl 
A solution of 1.0 eq of an arylboronic acid (or ester) and the appropriate aryl bromide (1.0 eq) in 2:1 toluene:ethanol (0.1 M concentration for each reagent) was sparged with nitrogen for 15 minutes. Tetrakis (triphenylphosphine)palladium (0) (0.05 eq) and 2 M aqueous sodium carbonate (3 eq) were added and the mixture was heated at 85xc2x0 C. for 3 h under a nitrogen atmosphere. The mixture was cooled and ethyl acetate and water were added. The organic layer was washed once with saturated aqueous sodium carbonate, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel using hexanes/ethyl acetate as eluant to yield the biaryl product.
Arylboronic acids used: [2-[[(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)-methyl]amino]-sulfonyl]phenyl]boronic acid (or the corresponding SEM-protected compound, both of which were prepared as described in U.S. Pat. No. 5,612,359); [2-[[(4,5-dimethyl-3-isoxazolyl)[(2-methoxyethoxy)methyl]amino]-sulfonyl]phenyl]boronic acid (prepared as described in U.S. Pat. No. 5,612,359 and U.S. patent application Ser. No. 09/013,952, filed Jan. 27, 1998); [2-(N-tert-butylsulfamoyl)phenyl]boronic acid (prepared according to Chang, L. L. et al., J. Med Chem., 38, 3741-3758 (1995)).
Arylboronate ester used: N-[(2-methoxyethoxy)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (prepared as described in WO 97/29747).
RCH2OHxe2x86x92RCH2Br 
To a 0.2 M solution of the alcohol in DMF at 0xc2x0 C. was added carbon tetrabromide (1.5 eq) followed by triphenylphosphine (1.5 eq). The mixture was stirred at 0xc2x0 C. for 4 h, diluted with 10 parts 2:1 hexanes/ethyl acetate, and washed with water and brine. The solution was dried over sodium sulfate and concentrated, and the residue chromatographed on silica gel using hexanes/ethyl acetate as eluant to yield the alkyl bromide product.
RCH2OHxe2x86x92RCH2OMs 
To a 0.15 M solution of the alcohol in dichloromethane at 0xc2x0 C. was added N,N-diisopropylethylamine (1.5 eq) followed by methanesulfonyl chloride (1.1 eq). The mixture was stirred at 0xc2x0 C. for 1 to 3 h, and was then treated with 10% aqueous potassium dihydrogensulfate. The aqueous layer was extracted once with dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated to yield the crude alkyl methanesulfonate.
RCH2Xxe2x86x92RCH2-heterocycle OR RCH2xe2x80x94ORxe2x80x2
X=Br, OMs 
Sodium hydride (60% dispersion in mineral oil, 1.2 eq) was added at 0xc2x0 C. to a 1.0 M solution or suspension of an appropriate heterocycle or alcohol (1.5 eq) in DMF. The mixture was allowed to warm to RT, was stirred for 20 min, and was then cooled back to 0xc2x0 C. To the heterocycle mixture was added a solution of the appropriate alkyl bromide or alkyl methanesulfonate (1.0 eq) in a minimal amount of DMF. The resultant mixture was allowed to warm to RT and was stirred for 16-24 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated, and the residue chromatographed on silica gel with hexanes/ethyl acetate as eluant to yield the alkylation product.
ArCHO+RNH2 [or RNH2.HCl]xe2x86x92ArCH2xe2x80x94NHR 
To a mixture of an aromatic aldehyde (1.0 eq) and a primary amine (1.2 eq) in dichloromethane (0.1 M aldehyde concentration) was added 4 xc3x85 molecular sieves (5 g per mmol aldehyde). [Alternately, a primary amine hydrochloride (1.2 eq) and triethylamine (1.2 eq) could be substituted for the primary amine free base.] The mixture was stirred vigorously for 1 h, after which sodium triacetoxyborohydride (1.5 eq) was added. The mixture was stirred vigorously at RT, while the course of the reaction was monitored by HPLC. If the reaction had not reached completion within several hours, additional sodium triacetoxyborohydride (1.0 eq) was added and monitoring was continued. When the reaction was complete the mixture was filtered through celite, aqueous sodium bicarbonate solution was added to the filtrate, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated. The crude residue was carried on without further purification.
In general, reductive amination with a 4-aminobutanoic acid resulted in a lactam product. In a few cases, cyclization was promoted by treatment of a 0.1 M solution of the crude amino acid product in dichloromethane with 1.0 eq of diisopropylcarbodiimide for 1 h at RT.

A 0.15 M solution of a primary or secondary amine (1.0 eq) and N,N-diisopropylethylamine (2.0 eq) in dichloromethane was treated at RT with an acyl chloride (1.5 eq). After 1.5 h, methanol (10 eq) was added, followed by aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane and the combined organic extracts were combined, dired over sodium sulfate, and concentrated. The residue was chromatographed on silica gel with hexanes/ethyl acetate as eluant to provide the product tertiary amide.

To a 0.1 M solution of a SEM- or MEM-protected N-heteroaryl sulfonamide in one volume of 95% EtOH was added an equal volume of 6N aqueous HCl, and the resulting solution was heated at reflux for 1 h. The reaction mixture was concentrated and the pH of the solution was adjusted to pH 8 using aqueous sodium bicarbonate solution. It was then reacidified to pH 5 with glacial acetic acid. The mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse-phase preparative HPLC, or by silica gel chromatography using chloroform/methanol or hexanes/acetone as eluant.

A solution of a SEM- or MEM-protected N-heteroaryl sulfonamide in one volume of absolute methanol or ethanol was treated with two volumes of 4 N hydrogen chloride/dioxane solution (final substrate concentration 0.05 M). The resulting solution was heated at 55xc2x0 C. for 16 h and was then concentrated. The residue was purified by reverse-phase preparative HPLC, or by extraction with ethyl acetate from aqueous potassium phosphate adjusted to pH 5-6, followed by silica gel chromatography.

To a 0.1 M solution of of a SEM- or MEM-protected N-heteroaryl sulfonamide in acetonitrile was added trimethylsilyl chloride (8 eq) followed by sodium iodide (8 eq). The mixture was stirred at RT for 30 min and was then poured onto water and ethyl acetate. The organic layer was washed with saturated sodium sulfite and brine, and was then dried over sodium sulfate and concentrated. The residue was purified by reverse-phase preparative HPLC or by silica gel chromatography.

To a 0.05 M solution of a SEM-protected N-heteroaryl sulfonamide in THF was added freshly activated 4 xc3x85 molecular sieves (20 g per mmol sulfonamide), followed by tetrabutylammonium fluoride (1.0 M solution in THF, 3 eq). The mixture was heated at 55xc2x0 C. for 1-2 h, then was cooled and filtered through celite. The filter cake was rinsed with methanol, then aqueous potassium dihydrogen phosphate solution was added to the filtrate and the mixture partially concentrated. The residue was adjusted to pH 4-5 using dilute hydrochloric acid, and the mixture was extracted with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase preparative HPLC or by silica gel chromatography.
ArCHOxe2x86x92ArCH2xe2x80x94OH 
Sodium borohydride (0.5 eq) was added at 0xc2x0 C. to a 0.2 M solution of an aromatic aldehyde in absolute ethanol or methanol. The mixture was allowed to warm to RT and stirred for 1-2 h. Aqueous potassium dihydrogen phosphate solution (or dilute hydrochloric acid) was added and the mixture was stirred for an additional 15 min. The mixture was partially concentrated and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried over sodium sulfate and concentrated. The crude benzylic alcohol was either used directly or was purified by silica gel chromatography using hexanes/ethyl acetate as eluant.

1,1xe2x80x2-Carbonyldiimidazole (2.0 eq) was added to a 0.1 M solution or suspension of an appropriate carboxylic acid (1.0 eq) in THF. The mixture was heated at 50xc2x0 C. for 1 h, and was then cooled to RT. An appropriate amine (5-10 eq) was then added, and the mixture was stirred at RT for 12 h. Ethyl acetate and aqueous sodium bicarbonate solution were added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase preparative HPLC or by silica gel chromatography.
ArCH3xe2x86x92ArCH2xe2x80x94Br 
To a 0.4 M solution of a methyl-substituted aromatic compound in carbon tetrachloride was added N-bromosuccinimide (1.05 eq) and benzoyl peroxide (0.03 eq), and the mixture was heated at reflux for 8-16 h. The mixture was cooled and filtered and the filtrate concentrated. The residue was purified by trituration with 3:1 hexanes/ethyl acetate, or by silica gel chromatography using hexanes/ethyl acetate as eluant to provide the mono-brominated product.
ArCNxe2x86x92ArCHO 
DIBAL-H (1.5 M solution in toluene, 1.5 eq) was added dropwise at 0xc2x0 C. to a 0.5 M solution of an aromatic nitrile (1.0 eq) in toluene or 9:1 toluene/dichloromethane. The solution was stirred at 0xc2x0 C. for 1-4 h, and was then treated with excess methanol. After 15 min, 2N hydrochloric acid was added and the mixture was stirred vigorously for an additional 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield the crude aldehyde, which was either carried on crude or purified via silica gel chromatography using hexanes/ethyl acetate as eluant.
RCOORxe2x80x2xe2x86x92RCOOH 
A 0.25 M solution of an alkyl ester in 1:1 THF/water was treated with lithium hydroxide hydrate (1.5 eq) at RT. The mixture was stirred for 8-16 h and was then acidified with dilute hydrochloric acid. The product was either isolated by direct filtration from the reaction mixture, or by extraction with ethyl acetate, followed by drying of the organic layers with sodium sulfate, concentration, and silica gel chromatography using methanol/chloroform or hexanes/acetone as eluant.
ArCH2Xxe2x86x92ArCH2xe2x80x94CN 
X=Br, OMs 
Sodium cyanide (1.2 eq) was added at RT to a 1.0 M solution of a benzylic bromide or mesylate in DMF. The mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and partitioned against aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated, and the residue chromatographed on silica gel with hexanes/ethyl acetate as eluant to yield the nitrile product.
ArCH2xe2x80x94OHxe2x86x92ArCHO 
Oxalyl chloride (1.5 eq) was added dropwise to a solution of DMSO (2.0 eq) in dichloromethane at xe2x88x9278xc2x0 C. After 5 min, a solution of benzylic alcohol substrate (1.0 eq) in dichloromethane was added and the mixture (0.2 M final substrate concentration) was stirred at xe2x88x9278xc2x0 C. for 15 min. Triethylamine (4.0 eq) was added and the mixture was stirred and allowed to warm to RT. Aqueous sodium bicarbonate solution was added, the layers were separated, and the aqueous layer was extracted with one portion of dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated, and the residue was purified by silica gel chromatography using hexanes/ethyl acetate as eluant.
ArNO2xe2x86x92ArNH2 
Tin (II) chloride dihydrate (4.0 eq) was added to a 0.05 M solution of an aromatic nitro compound in ethyl acetate and the resulting mixture was heated at 70xc2x0 C. for 45 min. The mixture was cooled, half-saturated aqueous sodium carbonate solution was added, and the layers were separated. The aqueous layer was extracted once with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using hexanes/ethyl acetate as eluant to provide the product aromatic amine.

A 0.2 M solution of a 2-aryl-1,3-dioxolane (1.0 eq) in THF was treated with 1N hydrochloric acid (1.5 eq), and the resulting solution was heated at 55xc2x0 C. for 16 h. The mixture was cooled and neutralized with aqueous sodium bicarbonate solution, then extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the crude aldehyde was used directly with no further purification.

1,1xe2x80x2-Carbonyldiimidazole (2.0 eq) was added to a 0.1 M solution or suspension of an appropriate carboxylic acid (1.0 eq) in THF. The mixture was heated at 50xc2x0 C. for 1 h. An appropriate alcohol (3.0 eq) was then added, followed by DBU (3.0 eq). The mixture was heated at 50xc2x0 C. for 16 h and was then cooled. Ethyl acetate and 35% aqueous citric acid solution were added, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase preparative HPLC or by silica gel chromatography.

A solution of an appropriate imidazole (0.1 M) in toluene was treated with 50% aqueous sodium hydroxide solution (0.5 ml per mmol imidazole), tetrabutylammonium hydrogen sulfate (0.05 eq), and an appropriate benzylic alkyl bromide or mesylate (0.95 eq). The mixture was stirred vigorously at 40xc2x0 C. for 24 h and was then cooled and filtered. Water was added and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to provide the crude product, which was either purified by silica gel chromatography or was carried on crude. Imidazole used: 2-propyl-4,5,6,7-tetrahydro-8-oxocycloheptimidazole (Yanagisawa, T.; et. al. Biorg. Med. Chem. Lett. 1993, 3, 1559-1564).

A solution of an appropriate imidazole (0.5 M) in DMF was treated with potassium carbonate (2.0 eq) and a benzylic alkyl bromide or mesylate (1.0 eq) at RT. The mixture was stirred at RT for 16 to 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated to provide the crude product, which was purified by silica gel chromatography or was carried on crude. When mixtures of N-1 and N-3 alkylation products were obtained, the regiochemistry of the alkylation was determined by NOESY spectroscopy.

To a 0.05 M solution of a SEM-protected N-heteroaryl sulfonamide in DMF was added cesium fluoride (5.0 eq), and the resulting mixture was heated at 130xc2x0 C. for 3 h. The reaction mixture was cooled and the solvent evaporated. Aqueous potassium dihydrogen phosphate solution was added (pH 4-5) and the mixture was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase preparative HPLC or by silica gel chromatography.
ArNH2xe2x86x92ArNHSO2R 
To a 0.1 M solution of an aromatic amine (1.0 eq.) in dichloromethane at xe2x88x9230xc2x0 C. was added triethylamine (2.6 eq), followed by a sulfonyl chloride (1.4 eq). The mixture was allowed to warm to RT over 3 hr. Aqueous sodium bisulfate was added (final pH 5) and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water and brine, and were then dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using dichloromethane/methanol as eluant.
ArCHOxe2x86x92ArCOOH 
A 0.1 M solution of an aromatic aldehyde in 1:1 THF/water was treated at 0xc2x0 C. with sulfamic acid (1.5 eq) and sodium chlorite (1.5 eq). After 1 h aqueous potassium bisulfate solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to provide the crude carboxylic acid, which was used without further purification.
Anion exchange chromatography was performed on Varian SAX cartridges (acetate form, 1.5-3 g) or United Chemical Technologies CUQAX13M6-AC cartridges (acetate form, 3 g). Following a methanol rinse, the cartridge was loaded with a dichloromethane solution of crude product. Elution of impurities with dichloromethane, followed by elution of the desired product with 1-3% TFA in dichloromethane or dichloromethane/methanol, provided the purified product.
Reverse-phase preparative HPLC was performed with Shimadzu 8A liquid chromatographs using YMC S5 ODS columns (20xc3x97100, 20xc3x97250, or 30xc3x97250 mm). Gradient elution was performed with methanol/water mixtures in the presence of 0.1% TFA. In some cases a product eluting as a TFA salt was subsequently converted to the corresponding free base by extraction from aqueous sodium bicarbonate or sodium carbonate solution.
Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographs using the following methods:
A. Linear gradient of 0 to 100% solvent B over 4 min, with 1 min hold at 100% B;
UV visualization at 220 nm
Column: YMC S5 ODS Ballistic 4.6xc3x9750 mm
Flowrate: 4 ml/min
Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol
Solvent B: 0.1% trifluoroacetic acid, 90% methanol, 10% water
B. Linear gradient of 0 to 100% solvent B over 30 min, with 5 min hold at 100% B;
UV visualization at 254 nm
Column: YMC S3 ODS 6xc3x97150 mm
Flowrate: 1.5 ml/min
Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol
Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water
C. Linear gradient of 0 to 100% solvent B over 4 min, with 1 min hold at 100% B
UV visualization at 220 nm
Column: YMC S5 ODS Ballistic 4.6xc3x9750 mm
Flowrate: 4 ml/min
Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol
Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water
D. Linear gradient of 45 to 100% solvent B over 2 min, with 1 min hold at 100% B;
UV visualization at 220 nm
Column: Phenomenex Primesphere 4.6xc3x9730 mm
Flowrate: 5 ml/min
Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol
Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water
E. Same conditions as (B), but with a linear gradient of 40 to 100% solvent B over 30 min, with 5 min hold at 100% B
F. Same conditions as (B), but with a linear gradient of 70 to 100% solvent B over 30 min, with 5 min hold at 100% B
G. Same conditions as (D), but with a linear gradient of 40 to 100% solvent B over 2 min, with 1 min hold at 100% B
H. Linear gradient of 0 to 100% solvent B over 2 min, with 1 min hold at 100% B;
UV visualization at 220 nm
Column: Phenomenex Primesphere 4.6xc3x9730 mm
Flowrate: 5 ml/min
Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol
Solvent B: 0.1% trifluoroacetic acid, 90% methanol, 10% water
I. Same conditions as (B), but with a linear gradient of 50 to 100% solvent B over 30 min, with 5 min hold at 100% B
J. Same conditions as (C), but with a linear gradient of 0 to 100% solvent B over 8 min, with 1 min hold at 100% B
K. Same conditions as (D), but with a linear gradient of 0 to 100% solvent B over 2 min, with a 1 minute hold at 100% B.

A. 4-Bromo-3-(bromomethyl)benzonitrile
The product was prepared according to General Method 13 starting from 12.0 g 4-bromo-3-methylbenzonitrile. Partial purification of the crude product was performed by trituration with 3:1 hexanes/ethyl acetate to afford 7.3 g of a slightly yellow solid, which was contaminated with approximately 20 mol % of the starting material.
B. 4-Bromo-3-(acetoxymethyl)benzonitrile
A mixture of P1A (7.3 g), potassium acetate (3.4 g), and DMF (10 ml) was stirred at RT for 16 h. Ethyl acetate was added and the mixture was washed with four portions of water, followed by one portion of brine. The ethyl acetate layer was dried over sodium sulfate and concentrated. The solid residue was partially purified by crystallization from ethyl acetate, yielding 4.5 g of a slightly yellow solid.
C. 4-Bromo-3-(hydroxymethyl)benzaldehyde
P1B (4.4 g) was treated with DIBAL-H according to General Method 14, using 3.5 eq of the reducing agent rather than 1.5 eq. The crude product was an orange oil (4.8 g), judged by 1H NMR to be approximately 75% pure by weight.
D. N-(3,4-Dimethyl-5-isoxazolyl)-4xe2x80x2-formyl-2xe2x80x2-(hydroxymethyl)-N-[(2-trimethylsiloxy)ethoxymethyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P1C (4.7 g) was subjected to Suzuki coupling according to General Method 1, yielding 7.6 g of the product as an orange oil following silica gel chromatography (2:1 hexanes/ethyl acetate eluant).

A. 4-Bromo-3-(bromomethyl)benzonitrile
The product was prepared according to General Method 13 starting from 19.6 g 4-bromo-3-methylbenzonitrile. After cooling the mixture was filtered and the filtrate was washed with H2O and brine, dried and concentrated. The residue was chromatographed on silica gel using 100:3 and then 100:10 hexane/EtOAc to afford P2A (16 g, 58%). Rf=0.15, silica gel, 10:1 hexane/EtOAc.
B. 4-Bromo-3-(Methoxymethyl)benzonitrile
To a solution of P2A (6.95 g, 25.28 mmol) in 10 ml DMF, NaOMe (25 wt. % in MeOH, 6.94 ml, 30.3 mmol) was added dropwise. The reaction mixture was stirred at RT for 3 h. Ethyl acetate (100 ml) and hexanes (50 ml) were added, and the mixture was washed twice with water and once with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using 100:6 hexane/EtOAc to afford P2B (4.70 g, 82%). Rf=0.5, silica gel, 5:1 hexane/EtOAc.
C. 4-Bromo-3-(methoxymethyl)benzaldehyde
P2B (7.0 g) was treated with DIBAL-H according to General Method 14, using THF instead of toluene as solvent. The crude product was purified by silica gel chromatography using 11:1 hexanes/ethyl acetate as eluant to give 6.2 g P2C as a colorless gum. Rf=0.4, silica gel, 5:1 Hexane/EtOAc.
D. N-(3,4-Dimethyl-5-isoxazolyl)-4xe2x80x2-formyl-2xe2x80x2-(methoxymethyl)-N-[(2-methoxyethoxy)methyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P2C (6.2 g) was subjected to Suzuki coupling according to General Method 1, giving P2D as an oil in 83% yield after silica gel chromatography.
E. N-(3,4-Dimethyl-5-isoxazolyl)-4xe2x80x2-hydroxymethyl-2xe2x80x2-(methoxymethyl)-N-[(2-methoxyethoxy)methyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P2D (2.8 g) was reduced with sodium borohydride according to General Method 11, to provide 2.8 g P2E.
F. N-(3,4-Dimethyl-5-isoxazolyl)-4xe2x80x2-bromomethyl-2xe2x80x2-(methoxymethyl)-N-[(2-methoxyethoxy)methyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P2E (2.8 g) was treated with triphenylphosphine and carbon tetrabromide according to General Method 2, providing the title compound (2.3 g) in 72% yield.

A. 4xe2x80x2-(Acetoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-2xe2x80x2-formyl-N-[(2-trimethylsiloxy)ethoxymethyl][1,1xe2x80x2-biphenyl]-2-sulfonamide acetoxime
Hydroxylamine hydrochloride (1.13 g) was added to a solution of 7.0 g P4 in 20 ml pyridine and the mixture was stirred at RT for 2 h. Acetic anhydride (5.1 ml) was added and the mixture was stirred for 1 h at RT. Ethanol (5 ml) was added and the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with 0.1 N hydrochloric acid, twice with half-saturated aqueous sodium carbonate solution, and once with brine. The ethyl acetate layer was dried over sodium sulfate and concentrated to provide P3A as an orange oil.
B. 4xe2x80x2-(Acetoxymethyl)-2xe2x80x2-cyano-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-trimethylsiloxy)ethoxymethyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P3A was dissolved in 75 ml acetonitrile, DBU (4.0 ml) was added, and the mixture was stirred at RT for 14 h. The mixture was concentrated, and the residue was taken up in ethyl acetate and washed twice with 0.1 N hydrochloric acid, then once with half-saturated aqueous sodium carbonate solution. The ethyl acetate layer was dried over sodium sulfate and concentrated to give P3B as an orange oil.
C. 2xe2x80x2-Cyano N-(3,4-dimethyl-5-isoxazolyl)-4xe2x80x2-(hydroxymethyl)-N-[(2-trimethylsiloxy)ethoxymethyl][1,1xe2x80x2-biphenyl]-2-sulfonamide
P3B was dissolved in 150 ml methanol, potassium carbonate (1.5 g) was added, and the mixture was stirred at RT for 2 h. 2N Hydrochloric acid (5.5 ml) was added and the mixture was concentrated. The residue was taken up in ethyl acetate and partitioned against aqueous sodium bicarbonate solution. The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 5.7 g of the crude title compound, which was used without further purification.
Preparations 4 through 22 were performed by application of the General Methods and are listed in the following Table.